Obesity in a young child can not only result in short-term social, psychological, and health effects but also increases the probability to obesity later n life with many possible accompanying chronic conditions such as cardiovascular disease, diabetes, and cancer. Both animal and human studies unequivocally show that perturbations during critical early periods of development can have a life-long, sometimes irreversible, adverse impact on markers of metabolic disease like adiposity and insulin resistance. Obesity's multi-factorial etiology along with developmental processes makes the links between early life factors and childhood obesity a complex system requiring a multi-disciplinary systems approach. Although the potential mechanism is not completely clear, epigenetic mechanisms may play an important role. Our work has shown considerable individual variability of DNA methylation patterns detectable at birth and dynamic in the first two years of life; and that maternal prepregnancy BMI is associated with offspring DNA methylation alterations at birth relevant to chronic disease. However, no study has traced pathways from early life factors through epigenetic changes at birth and early childhood to the development of childhood obesity and related phenotypes among urban low- income African American and Hispanic children who have been disproportionally affected by the obesity epidemic. The first aim of this application is to identify early life risk and protective factors for obesity development. We will investigate a comprehensive array of prenatal and birth to 24-month factors in the development of obesity by leveraging the extensive existing databases and ongoing follow-up of 3,000 Boston Birth Cohort (BBC) children from birth to age 10 years. We will pay particular attention to those potentially important factors that require further study. The second aim is to explore the mediating effect of the epigenome between early life factors and childhood obesity, using existing genome-wide DNA methylation data measured at birth and age 2 years (discovery sample); and replicate important findings by pyrosequencing in an independent sample. The third aim is to develop a Virtual Birth Cohort (VBC) systems dynamics model to represent and help better understand the complex system connecting early life factors with subsequent childhood obesity and determine the key modifiable factors that will most impact the subsequent development of childhood obesity; and test the intervention effects if modifying these factors to different degrees under a variety of scenarios. This highly innovative and efficient approach integrates real data from the BBC and then incorporates into a computational simulation model to better understand early life determinants of childhood obesity and epigenetic mechanisms. The VBC also will allow us to explore how findings from the BBC may apply to other locations and circumstances, thus helping generalize our findings. The impact of this project lies in the potential to inform new and sustainable strategies to reduce the burden of childhood obesity during the most critical developmental windows and among the most vulnerable segments of the US population.